title: Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.
abstract: Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep.
authors.affiliation: Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Nair
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramesh
authors.forename: Richard C
authors.initials: RC
authors.lastname: Li
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: David
authors.initials: D
authors.lastname: Gozal
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000523:psychology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003863:Depression / Q000209:etiology / Q000523:psychology; D004921:Erythropoietin / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007859:Learning Disabilities / Q000209:etiology / Q000523:psychology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017337:Sermorelin / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction; D012890:Sleep
chemical_list: C550121:GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004921:Erythropoietin; D017337:Sermorelin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013007:Growth Hormone-Releasing Hormone; D017526:Receptor, IGF Type 1; D003849:Deoxyguanosine
keywords: 8-hydroxydeoxyguanosine; Morris water maze; cortex; hippocampus; intermittent hypoxia; malondialdehyde